Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) are major control switches in the protein networks that govern cell signaling, movement, differentiation, and other processes. These enzymes thus play central roles in normal development as well as in cancer (many oncogenes are PTKs), diabetes (the insulin receptor is a PTK), and other diseases. The fly Drosophila melanogaster provides a powerful model system to study the role of PTPs in cancer-related processes such as epithelial development, cell migration, growth factor signaling, and apoptosis. A molecular genetic analysis is proposed to elucidate the functions of two Drosophila PTPs, named Pez and Meg after their human orthologs. Pez and Meg are FERM-PTPs, modular proteins that contain a FERM (4.1, ezrin, radixin, moesin-like) domain, a PTP domain, and additional protein binding motifs. Like other FERM domain proteins, Pez has affinity for discrete regions of the cell cortex and appears to participate in multiprotein complexes important for cell adhesion, actin organization, and cell motility/shape changes, all processes that are relevant to tumor metastasis. Pez can also regulate PTK activity. To understand how these activities are performed and integrated, three aims will be pursued. 1) Pez-containing protein complexes will be analyzed to determine their components and activities. Behavior of Pez and Meg will be compared, to understand how these related proteins may have become specialized for different functions. 2) Mutant animals that lack Pez will be studied by confocal microscopy to determine the specific cellular and developmental requirements for this PTP. 3) The FERM and PTP domains will be expressed separately in order to determine if either is sufficient to carry out the activities of wild type Pez. This information will contribute to understanding of both the FERM and PTP superfamilies. Since FERM-PTPs have not been analyzed by gene knockout in any organism, these experiments will provide novel insights into their role in normal and abnormal cell behaviors. A study of the regulation of tyrosine kinase/phosphatase signaling is proposed. This type of molecular communication system allows cells to properly interact with their neighbors in a cell sheet. Failure to regulate this system leads to metastatic cancer, diabetes, and other diseases. [unreadable] [unreadable] [unreadable]